1. Field of the Invention
This invention relates to a process for preparing a radioactive arsenic-containing compound and uses of the radioactive arsenic-containing compound in the treatment of tumors/cancers such as hematological malignancies and solid tumors. Particularly, an arsenic-containing compound selected from a group consisting of As2O3, As2S3, As2S2 and a combination thereof is subjected to a neutron irradiation treatment such that the arsenic element contained in the arsenic-containing compound is converted to a radioactive arsenic isotope. The radioactive arsenic-containing compound can be formulated into a pharmaceutical composition for the treatment of tumors/cancers, such as hematological malignancies and solid tumors.
2. Description of the Related Art
Tumors/cancers have always been a threat to the health of human beings. For many years, the medicinal field has endeavored to research and develop effective medicines for the treatment of tumors/cancers. However, up to the present, there is not any medicine that is effective in the clinical treatment of tumors/cancers, particularly in the treatment of liver tumor-related diseases (such as hepatocellular carcinoma).
At present, the cell therapy for metastasized liver cancer or liver cancer that has undergone unsuccessful localized treatment is mainly performing a transcatheteral arterial embolization (TAE) or a percutaneous ethanol injection, or adopting a systemic chemotherapy, such as administration of doxorubicin, a combination of tamoxifen in high dose and doxorubicin, or combined chemotherapy (cisplatin+5-FU+leucovorin, abbrev. PFL). Although the remission rate of these anti-cancer medicines can be up to 15˜30%, since most of the liver cancer patients have liver cirrhosis and/or other complications (such as leukocyte reduction, platelet reduction, or liver function decompensation), systemic chemotherapy is not suitable for such patients. Therefore, chemotherapy is unable to effectively extend the overall survival of patients suffering from liver cancer. Since 1990, arsenic-containing compounds (arsenicals) have provided another direction for research and development in the treatment of tumors/cancers.
It was reported that when arsenic trioxide was administered intravenously at a dose of 10 mg/d to patients with relapsed acute promyelocytic leukemia, a complete remission (CR) rate of 90% could be achieved. (See Shen Z. X. et al., Blood (1997), 89: 3354). It was also reported that, other than arsenic trioxide, arsenic-containing substances such as “Composite Indigo Naturalis Tablets” containing arsenic sulfide (As2S2) and pure tetraarsenic tetraslfide (As4S4) can achieve complete remission rates of 98% and 84.9%, respectively. (See Wang Z. Y., Cancer Chemother Pharmacol (2001), 48 (suppl 1): S72-S76).
Clinical studies further indicated that low-dose arsenic trioxide administered intravenously to patients with relapsed acute promyelocytic leukemia at a daily dose of 0.08 mg/kg for 28 days could achieve a complete remission rate of 80%, and that side effects caused by arsenic trioxide (such as gastrointestinal disturbance, facial edema and cardiac toxicity) were reduced. (See Shen Y, et al., Leukemia (2001), 15: 735-741).
It was also reported that for patients with relapsed acute promyelocytic leukemia or all-trans-retinoic acid (ATRA) resistant acute promyelocytic leukemia, the administration of a combination of arsenic trioxide and other drugs (such as GM-CSF) resulted in a synergistic therapeutic effect. (See Muto A et al., Leukemia (2001), 15(8): 1176-1184).
In recent years, the medical field has gradually explored the mechanism of arsenic trioxide in the treatment of acute promyelocytic leukemia. According to reports, the mechanism of arsenic trioxide in inhibiting acute promyelocytic leukemia cell lines may be the triggering of apoptosis at relatively high concentrations (from 0.5 to 2 μmol/L) and the induction of cell differentiation at low concentrations (from 0.1 to 0.5 μmol/L). (See Chen G Q, et al., Blood (1997), 89: 3345).
In 2002, Miller et al., propounding the possible mechanisms of actions of arsenic trioxide in Cancer Research (2002), 62:3893-3903, stated that these actions might result in the induction of apoptosis, the inhibition of growth and angiogenesis, and the promotion of differentiation, and that because arsenic affected so many cellular and physiological pathways, a wide variety of malignancies, including both hematologic cancer and solid tumors derived from several tissue types, might be susceptible to therapy with arsenic trioxide.
In 2001, the National Institutes of Health (NIH) of the United States proceeded with clinical trials of arsenic trioxide in hematologic and solid tumors, and indicated in their reports that arsenic trioxide can inhibit growth of many cancer cell lines, and promote apoptosis in the cancer cell lines. The clinical trials of arsenic trioxide conducted in connection with hematologic malignancies include, in addition to acute promyelocytic leukemia, acute myeloid leukemia (AML), acute lymphocytic leukemia, chronic myelogenous leukemia (CML), non-Hodgkin's lymphoma, Hodgkin's lymphoma, chronic lymphocytic leukemia, myelodysplastic syndrome and multiple myeloma. The clinical trials of arsenic trioxide conducted in connection with solid tumors include prostate cancer, cervical cancer and bladder cancer. (See Murgo A. J., The Oncologist (2001), 6 (suppl 2):22-28).
In September 2000, the Food and Drug Administration (FDA) of the United States approved arsenic trioxide as an orphan drug for treating acute promyelocytic leukemia. The Department of Health (DOH) of Taiwan, R.O.C., approved marketing of an arsenic trioxide-containing pharmaceutical preparation (“ASADIN Injection”; license no. 000005) by TTY Biopharm Co., Ltd. (Taiwan), in January, 2002.
In recent years, studies on the treatment of solid tumors with arsenic trioxide have gradually developed in China. It was indicated in a report that in an evaluation of the therapeutic efficacy of arsenic trioxide using an animal model of mice with liver tumor, the result showed that the life of the mice could be extended to 127.2% after administration of arsenic trioxide at a dose of 2 mg/kg for 10 consecutive days. (See Lin et al., “Study on Anti-tumor Activity of Arsenic Trioxide,” China Journal of Chinese Materia Medica (1999), 24(3): 1-3).
WO 99/24029 (corresponding to CN 1285743A) discloses methods for the treatment of leukemia, lymphoma, and solid tumors, which includes administering to a patient a therapeutically effective amount of arsenic trioxide or an organic arsenical, i.e. melarsoprol, which can be used in combination with other therapeutic agents (such as chemotherapeutics, radioprotectants, radiotherapeutics or other medical techniques so as to improve the quality of life of the patient. In addition, the pharmaceutical composition used in the aforesaid patent is a substantially sterile solution suitable for intravenous injection or infusion, and is also suitable for oral delivery, or topical or transdermal delivery. The preparation of the sterile solution involves the adjustment of specific pH values.
In the treatment of tumors/cancers, in addition to chemotherapeutics, radiation has been used by the medical field in the diagnosis and treatment of diseases, particularly in the treatment of cancers (such as skin cancers and nasopharyngeal cancers) since the discovery of the radioactive Ra element (226Ra) by the Curies in 1898. With the development in the research of the radionuclide science after World War II, scientists have gained a better understanding of the effects of radiation on living creatures, which has further improved methods and techniques of radiation therapy, increased the rate of survival, and prolonged lifespan, while reducing the side effects of radiation on normal tissues.
Internal radionuclide therapy (IRT) works by the principle of delivering large radiation doses to the targeted diseased tissues by using appropriate radiopharmaceuticals (RPs) while sparing normal tissues. For selective localization, either ions or molecules that are specific to diseased tissues are used as carriers for therapeutic radionuclides or soluble and microparticulate radiopharmaceuticals (RPs) are introduced regionally to increase uptake or to confine the RP in a body cavity.
Radionuclides for therapeutic use should be able to emit radiations that have high linear energy transfer (LET) in order to destroy malignant and other rapidly proliferating cell populations. They include (1) β emitting radionuclides, (2) α emitting radionuclides and (3) radionuclides that decay by electron capture (EC) and internal conversion (IC) to result in the emission of Auger and Coster-Kronig (C-K) electrons. The range of β particles is in mm's so that they are effective for large tumors. The range of α particles is 50-100 μm so that they are effective for small tumors and micrometastases. Radionuclides that emit Auger and C-K electrons are effective only when they are carried across the cell membrane into the nucleus to damage DNA, because the range of these electrons is <0.1 μm.
The aforesaid is based on the review article by Meral Tayan Ercan and Meltem Caglar in Current Pharmaceutical Design (2000), 6:1085-1121. Various radionuclides are listed in tables 1 and 2 of said review article, including 32P, 67Cu, 76As, 89Sr, 90Y, 131I, 153Sm, 165Dy, 166Ho, 169Er, 186Re, 188Re, 198Au, 211At, 212Bi and 213Bi, of which 131I is the most widely used therapeutic radiopharmaceutical and is used for the treatment of thyroid cancer and hyperthyroidism. Table 3 of said review article also mentioned several radionuclides, which are prepared in specific forms of therapeutic radiopharmaceuticals for particular applications. However, said review article is silent on the preparation of therapeutic radiopharmaceuticals from arsenic-containing compounds, such as arsenic trioxide, arsenic trisulfide and arsenic sulfide.
In 2002, Yong-Jin Chun et al., described in FEBS Letter, (2002), 519: 195-200, that arsenic trioxide can sensitize human cervical cancer cells to ionizing radiation both in vitro and in vivo, and that the combined treatment of arsenic trioxide in chemotherapy and ionizing radiation has a synergistic effect in the treatment of cervical cancer.
All literatures and patents mentioned hereinabove, as well as the literatures cited therein, are incorporated herein by reference in their entirety.